QSAR Flex, MultiCASE Inc.
N-Nitroso Varenicline |
| - CPCA Prediction -
Potency Category: 3 |
Potency Category 3: N-nitrosamines in this category have lower carcinogenic potency compared to Potency Category 2 due to, for example, the presence of a weakly deactivating structural feature. The recommended AI limit was set to reflect a 4-fold decrease in carcinogenic potency from Category 2.
This N-nitrosamine (NNV, Varenicline, N-nitroso) already has an assigned classification by the regulatory agencies: US FDA - 400 ng/day, Health Canada - 400 ng/day, European Medicines Agency - 400 ng/day.
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A surrogate (NTHP, N-nitroso-1,2,3,6-tetrahydropyridine, TD50 = 0.03 mg/kg/day) with robust animal carcinogenicity study data is available for this N-nitrosamine (see below). Relevant structural features of this surrogate have a 100% match with the query nitrosamine.
Potency Prediction Workflow
|
Does the N-Nitrosamine have any hydrogens on its α-Carbons
Yes
Does the N-Nitrosamine have more than one α-hydrogen on one or both sides of the N-nitroso group?
Yes
Does the N-Nitrosamine have a tertiary α-carbon?
No
Potency Score Calculation
α-Hydrogen Score (1) + Deactivating Feature Score (2) + Activating Feature Score (0) = 3 Potency Category 3
AI = 400 ng/day |
α-Hydrogens
Deactivating Features
Deactivating Feature Score = 2 No Activating Features were identified |
Query Nitrosamine
CPCA AI: 400 ng/day
α-H count: (2, 2)
α-H score = 1
Deactivating feature score = 2
Activating feature score = 0
| Surrogate1 | TD50 (mg/kg/day) |
Robustness of Carcinogenicity Study2 |
Regulatory AI (ng/day) |
Predicted CPCA AI (ng/day) |
α-H Count & Score |
Feature Scores |
|---|---|---|---|---|---|---|
|
Sim. = 1.000 55556-92-8 NTHP, N-nitroso-1,2,3,6-t... | 0.03 | ★★★ | HC = 37 EMA = 37 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
|
Sim. = 1.000 100-75-4 NPIP, N-Nitrosopiperidine | 1.33 | ★★★ | HC = 1300 EMA = 1300 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
|
Sim. = 1.000 140-79-4 1,4-Dinitrosopiperazine | 1.16 | ★★ | HC = 400 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
|
Sim. = 1.000 5632-47-3 NPZ, 1-Nitrosopiperazine | 28.5 | ★★ | US FDA = 1300 HC = 400 EMA = 400 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
|
Sim. = 1.000 16339-07-4 MeNP, 1-Methyl-4-nitrosop... | 0.14 | ★ | US FDA = 400 HC = 400 EMA = 400 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
1Sim. - A similarity value which is a function of common structural features (based on the CPCA method) between the query and the surrogate nitrosamine.
2★★★ - Robust carcinogenicity study, ★★ - Limited but sufficient carcinogenicity study, ★ - Insufficient carcinogenicity Data; Robustness criteria based on Bercu et al., Regulatory Toxicology and Pharmacology, 142 (2023) 105415.
Query Nitrosamine
CPCA AI: 400 ng/day
α-H count: (2, 2)
α-H score = 1
Deactivating feature score = 2
Activating feature score = 0
| NDSRI1 | Regulatory AI (ng/day) |
Predicted CPCA AI (ng/day) |
α-H Count & Score |
Feature Scores |
|---|---|---|---|---|
|
Sim. = 1.000 exact hit 2755871-02-2 NNV, Varenicline, N-nitro... | US FDA = 400 HC = 400 EMA = 400 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
|
Sim. = 1.000 Clozapine EP Impurity C, ... | HC = 400 EMA = 400 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
|
Sim. = 1.000 Terazosin EP Impurity C, ... | HC = 400 EMA = 400 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
|
Sim. = 1.000 2221987-86-4 1-(2,3-dichlorophenyl)-4-... | HC = 400 EMA = 400 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
|
Sim. = 1.000 1-(2-ethoxyethyl)-2-(1-ni... | HC = 400 EMA = 400 | 400 | (2, 2) Score = 1 | Deact. = 2 Act. = 0 |
1Sim. - A similarity value which is a function of common structural features (based on the CPCA method) between the query and the NDSRI.